Kevan Shokat ’86 Finding a Pathway for KRas Inhibition

Wikipedia: The protein product of the KRas gene performs an essential function in normal tissue signaling: it acts as a molecular on/off switch. In the ‘on’ position, KRas recruits and activates proteins necessary for the propagation of growth factor and other signaling pathways, however, the mutation of a KRas gene also happens to be an essential step in the development of many cancers.

C&EN (6 June 2016, cover story): “KRas, part of a family of proteins commonly mutated in cancer, is one of the most desirable drug targets in the pharmaceutical industry. It is also one of the most maddeningly difficult targets; after a long period of failures, many scientists simply stopped trying to develop drugs that block KRas.”

The C&EN cover story also describes how the first real break in the KRas story came in December 2011, when Dr. Ulf Peters, a postdoc in the Shokat lab at UC San Francisco, was able to determine an x-ray structure of a KRas-small molecule complex. Peters sent the coordinates to Shokat by email, but what he didn’t know was this: Shokat had been caught in an early winter Lake Tahoe snowstorm, and was stuck in his car at the bottom of a slick, steep hill. Finally, once this obstacle had been overcome, and Shokat had located a computer, he was able to download Peters’ 3-D structure, which struck him as, “just, like, unbelievable.” The structure revealed a previously unknown “shallow pocket” that functioned as an allosteric binding site, and it gave Shokat’s team the toehold it needed to design the first covalent inhibitor of the KRas protein.